EP2068838A1 - Pharmaceutical formulations comprising clopidogrel - Google Patents

Pharmaceutical formulations comprising clopidogrel

Info

Publication number
EP2068838A1
EP2068838A1 EP07818184A EP07818184A EP2068838A1 EP 2068838 A1 EP2068838 A1 EP 2068838A1 EP 07818184 A EP07818184 A EP 07818184A EP 07818184 A EP07818184 A EP 07818184A EP 2068838 A1 EP2068838 A1 EP 2068838A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
melt
clopidogrel
melt granulate
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP07818184A
Other languages
German (de)
French (fr)
Other versions
EP2068838B1 (en
Inventor
Hélène Rey
Marc Fischer
Mathias Scheer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acino Pharma AG
Original Assignee
Acino Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Acino Pharma AG filed Critical Acino Pharma AG
Priority to EP11003617A priority Critical patent/EP2359810A2/en
Priority to PL07818184T priority patent/PL2068838T3/en
Priority to EP07818184A priority patent/EP2068838B1/en
Publication of EP2068838A1 publication Critical patent/EP2068838A1/en
Application granted granted Critical
Publication of EP2068838B1 publication Critical patent/EP2068838B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

Melt granulate in the form of a solid state dispersion of the drug in a pharmaceutically acceptable carrier, wherein said melt granulate comprises a pharmaceutically active compound, preferably clopidogrel, at least one carrier material, and optionally pharmaceutically acceptable excipients and method of making said melt granulate.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING CLOPIDOGREL
The present invention relates to certain pharmaceutical formulations comprising clopidogrel or a pharmaceutically acceptable salt thereof, processes for their manufacture and their use in a method of treating warm-blooded animals, including preferably mammals and especially humans.
BACKGROUND OF THE INVENTION Clopidogrel is methyl (+)- (S) -alpha- (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate (= d-enantiomer) of the following formula:
πVv e
It is marketed in the form of its bisulfate by Sanofi under the trade name PLAVIX® (INN: clopidogrel bisulfate) , inter alia as an antiplatelet drug.
The racemic form of clopidogrel of the formula
in which the C* is an asymmetric carbon atom in both (R)- and (S) -configuration, and its pharmaceutically acceptable salts are described in US 4,529,596 and EP 099 802.
The dextro-rotatory enantiomer (= d-enantiomer) of methyl alpha- 5- (4 , 5, 6, 7-tetrahydro (3, 2-c) thieno-pyridyl) - (2-chlorophenyl) - acetate and certain of its pharmaceutically acceptable salts, like especially its bisulfate, are described in US 4,847,265 and EP 0 281 459.
According to US 4,847,265 many salts of clopidogrel have the drawback of being hygroscopic and difficult to handle on an industrial scale, and their purification proved to be difficult. EP 1 310 245 mentions that magnesium stearate should not be used as a lubricant together with clopidogrel because generally there is an interaction between clopidrogrel bisulphate and magnesium stearate causing degradation and instability of clopidogrel tablets which contain magnesium stearate.
DESCRIPTION OF THE INVENTION
It has now surprisingly been found how the above-mentioned drawback can be overcome. According to the present invention clopidogrel and its pharmaceutically acceptable acid addition salts can be stabilized in pharmaceutical formulations comprising melt granulates.
As shown in the Detailed Description of Experiments hereinafter, the stabilizing effect of the melt granulate formulations is so pronounced that it allows using also those pharmaceutically acceptable acid addition salts of clopidogrel which have been described in US 4,847,265 as being unsuitable, e.g. the salt with benzenesulfonic acid, i.e. the besylate. Even more surprisingly, the stabilizing effect of the melt granulate formulations is especially pronounced for clopidogrel salt batches of bad quality. This is especially valuable for salts the purification of which proves to be difficult. For example, as evident from Table 2 in Example 10 herein clopidogrel hydrochloride contains after storage for 30 days at 400C and 75% relative humidity nearly twice as much impurities than the clopidogrel hydrochloride stabilized in the melt granulates of the present invention. Hence, the formation of the melt granulates of the present invention surprisingly markedly reduces degradation of clopidogrel and its salts on storage.
The acid addition salts of clopidogrel which can be stabilized according to the present invention are those with pharmaceutically acceptable mineral or organic acids classically used in pharmacy. Appropriate acids are, for example, inorganic acids, such as hydrohalic acid, e. g. hydrochloric, hydrobromic or the like, or sulfuric acid, nitric acid, or phosphoric acid; or suitable organic acids, for example suitable aliphatic acids, like aliphatic mono or dicarboxylic acids, hydroxyalkanoic or hydroxyalkanedioic acids, e.g. acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z) -2-butenedioic, (E) -2-butenedioic, 2-hydroxy- butanedioic, 2, 3-dihydroxybutanedioic, or 2-hydroxy-l, 2, 3-pro- panetricarboxylic acid; phenylsubstituted alkanoic acids; or suitable aromatic acids, like 2-hydroxybenzoic, or 4-amino-2- hydroxybenzoic acid; or suitable sulfonic acids, like alkane- sulfonic acids, e.g. methanesulfonic, or ethanesulfonic acid, or aromatic sulfonic acids, e.g. benzenesulfonic, or 4-methyl- benzenesulfonic acid; or cyclohexanesulfamic acid. Preferred acids are e.g. hydrobromic acid, sulphuric acid, phosphoric acid, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, dobesilic, methanesulfonic, ethanesulfonic, lauryl- sulfonic, and para-toluenesulfonic acids, especially hydrochloric acid, and most especially benzenesulfonic acid.
The term "pharmaceutically acceptable salt" as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoro- acetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitro- benzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, nitrate, oxalate, phthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, meta- phosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate (hydrogensulfate) , pyro- sulfate, sulfite, bisulfite, sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfo- nate, methanesulfonate (mesylate) , naphthalene-1- sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate (tosylate) , xylene- sulfonate, tartarate, and the like. Preferred salts are the hydrochloride (chloride) and the benzenesulfonate (besylate) .
These salts are prepared in a standard manner, for example by the action of the corresponding acid on clopidogrel base in solution in a solvent from which they precipitate spontaneously or after addition of a non-solvent of the salt.
The term "melt granulate" as used herein defines a solid state dispersion of the active ingredient, i.e. clopidogrel or its pharmaceutically acceptable acid addition salts, i.e. the "drug", in an inert or pharmaceutically acceptable carrier or matrix prepared by a melting (fusion) method. The dispersion of the active ingredient in a solid carrier or diluent by traditio- nal mechanical mixing is not included within the definition of this term.
The term "pharmaceutically acceptable excipients" as used herein defines the excipients which may be added to the melt or later to the solid state dispersion of the drug in the pharmaceutically acceptable carrier, i.e. to the melt granulate, e.g. for tabletting. As used herein, the term "pharmaceutically acceptable carrier" refers preferably to suitable polyethylene glycols (PEGs) as defined herein below. Further carriers which can be used in accordance with the present invention include e.g. Compritol 888 ATO. Compritol [trade mark] is designated in The National Formulary (NF) as glyceryl behenate, and according to the International Nomenclature of Cosmetic Ingredients [INCI] as Tribehenin. It is obtainable for example from the company Gatte- fosse. Compritol is a mixture of esters of glycerol with Ci6-C22 fatty acids, mainly with C22 fatty acid, i.e. behenic acid.
Polyethylene glycols, also called macrogols, are manufactured by polymerization of ethylene oxide with either water, monoethylene glycol or diethylene glycol under alkaline catalysis. After the desired molecular weight is reached (according to viscosity measurements) the reaction is terminated by neutralizing the catalyst with an acid. The result are molecules of the structure HO-[CH2-CH2-O]n-H wherein n is the number of ethylene oxide units .
As an abbreviation for polyethylene glycols the term "PEG" is used in combination with a numerical value which, within the pharmaceutical industry, indicates the mean molecular weight. Unfortunately, the various Parmacopeias use different nomen- clature for some PEG molecular weights. The molecular weights cited herein are in accordance with the European (2002) and US Pharmacopeias. The hardness of PEGs increases with increasing molecular weight, however the melting range goes up to a maximum value of about 600C only. The most important property of all PEGs is their solubility in water. The lower PEGs up to a molecular weight below about 2000 are hygroscopic. PEGs can be obtained for example from the company Clariant, Switzerland. Suitable PEGs for the manufacture of melt granulates according to the present invention have a molecular weight from about 1500 to 35000. Preferred are PEGs having a molecular weight from about 2000 to 20000, especially from about 4000 to 20000, more especially from about 4000 to 10000, e.g. 6000.
In this sense, the present invention provides a melt granulate, i.e. a pharmaceutical composition in the form of a solid state dispersion of the drug in a pharmaceutically acceptable carrier, said melt granulate comprising a pharmaceutically active compound, i.e. clopidogrel, at least one carrier material, and optionally pharmaceutically acceptable excipients.
Usually, the general method for preparation of a solid dis- persion proceeds by a fusion process wherein a pharmaceutically acceptable carrier is mixed with the drug to form an intimate mixture. The mixture is heated at or near the temperature of the melting point of the pharmaceutically acceptable carrier, thus forming a melt. However, the mixture is heated sufficiently below the melting point of the pharmaceutically active compound, i.e. clopidogrel, in order to avoid any decomposition of the compound. The molten mixture is then cooled rapidly to provide a congealed mass which may subsequently be milled to produce a powder .
Alternatively, the pharmaceutically acceptable carrier can be heated to molten condition upon which the drug can be added to the molten carrier or vice versa under stirring or mixing, e.g. in a high shear mixer, like a Diosna mixer, thus forming a molten homogeneous melt. Preferably, the molten carrier is added to the drug under stirring or mixing.
Lastly, the process proceeds by cooling the molten homogeneous melt to form a solid state dispersion. Cooling can be effected by conventional methods or, according to the preferred method of the present invention, by shock cooling, for example by adding, in a high shear mixer, dry ice, i.e. solid carbon dioxide having a temperature of about -78°C, preferably in the form of a kind of snow ("dry snow") , or liquefied air, preferably solid carbon dioxide, to the dispersion which thereupon breaks apart into many small particles which are sieved, e.g. through 1-2 mm. If cooling is carried out slowly, the average particle size obtained generally is too large so that subquent milling of the product is required. It was surprising to find that the addition of solid carbon dioxide or liquefied air to the melt yielded the required average particle size without destabilizing the active product .
The present invention refers to a method of making a pharmaceutical composition in the form of a solid state dispersion of a pharmaceutically active compound (drug) in a pharmaceutically acceptable carrier in the form of a melt granulate, said melt granulate comprising a pharmaceutically active compound, preferably clopidogrel, at least one carrier material, and optionally pharmaceutically acceptable excipients, characterized in that the pharmaceutically acceptable carrier is mixed with a pharmaceutically active compound, and optionally also with the pharmaceutically acceptable excipients, to form an intimate mixture, the obtained mixture is then heated at or near the temperature of the melting point of the pharmaceutically acceptable carrier but below the melting point of the pharmaceutically active compound, thus forming a melt, the obtained melt is then cooled rapidly to provide a congealed mass which optionally is milled to produce a powder.
The present invention also refers to a method of making a pharmaceutical composition in the form of a solid state dispersion of a pharmaceutically active compound in a pharmaceuti- cally acceptable carrier in the form of a melt granulate, said melt granulate comprising a pharmaceutically active compound, preferably clopidogrel, at least one carrier material, and optionally pharmaceutically acceptable excipients, characterized in that the pharmaceutically acceptable carrier, optionally containing pharmaceutically acceptable excipients, is heated at or near the temperature of the melting point of the pharmaceutically acceptable carrier but below the melting point of the pharmaceutically active compound; the molten pharmaceutically acceptable carrier is then mixed with the pharmaceutically active compound until a homogeneous melt is formed; the obtained melt is then cooled rapidly to provide a congealed mass which optionally is milled to produce a powder. Preferably, the molten carrier is added to the drug under stirring or mixing.
The obtained melt is cooled rapidly. This cooling process proceeds by cooling the molten homogeneous melt to form a solid state dispersion. Said cooling can be effected by conventional methods. Preferred, however, is the cooling by a shock cooling, preferably by adding, preferably in a high shear mixer, dry ice, i.e. solid carbon dioxide, having a temperature of about -78°C, preferably in the form of a kind of snow ("dry snow"), or liquefied air, preferably solid carbon dioxide, to the dispersion which thereupon cools rapidly and breaks apart into many small particles which can be sieved, e.g. through 1-2 mm.
The ratio of the drug to the pharmaceutically acceptable carrier can be varied over a wide range and depends on the concentration of the drug required in the pharmaceutical dosage form ulti- mately administered. However, the preferred range of the drug in the solid dispersion is about 10% to 90% of the total solid dispersion weight, more preferable is about 20% to 90%, even more preferable is about 40% to 90%, especially about 50% to 90%, e.g. 50, 60, 70 or 80%, of the total dispersion weight. Examples of pharmaceutically acceptable excipients include diluents resp. fillers (e.g. Pharmatose® DCL 11), binders, disintegrants (e.g. Explocel®) , coloring agents, flavoring agents, lubricants (e.g. Cutina®HR, a hydrated castor oil, or e.g. magnesium stearate) and/or preservatives. The excipients may be added to the melt or later to the solid state dispersion of the drug, e.g. for tabletting resp. compressing.
The pharmaceutical composition may be formulated by conventional methods of admixture such as blending, filling, granulation and compressing.
Besides acting as carriers for the active ingredient, PEGs also act as lubricants and binders during the tablet processing and solid PEGs are also frequently used in tablet coatings. These other uses of PEGs are distinguishable and have to be clearly distinguished from the use in the formation of melt granulates.
The medicine of the invention can be made available for oral administration for example in the form of tablets, which may be coated, like e.g. sugar-coated, or capsules.
The melt granulates and pharmaceutical compositions of the present invention may be used to treat warm-blooded animals, including mammals and humans, for the same indications which can be treated by PLAVIX, e.g. on account of its interesting inhibitory properties towards platelet aggregation and its interference in the mechanism of formation of arterial and venous thromboses. The medicine of the invention can be usefully administered in the treatment and prevention of platelet disorders, including for example also those due to extracoporeal blood circuits or the consequence of complications in atheroma. Mainly, the melt granulates of the present invention may be used for the manufacture of pharmaceutical compositions for reduction of atherothrombotic events in case of recent myocardial infarction, recent stroke, established peripheral arterial disease, and acute coronary syndrome.
The composition is usually presented as a unit dose composition containing from 30 to 100 mg, more usually from 60 to 90 mg, preferably 75 mg of clopidogrel. Such composition is normally administered once daily to a warm-blooded animal, including a human, of about 70 kg body weight, or as recommended for PLAVIX. As usual, the exact dose to be administered depends inter alia on the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. The treatment of patients with acute coronary syndrome should be initiated with a single 300 mg loading dose of clopidogrel and then continued at 75 mg once daily. In addition, Aspirin and/or heparin may be administered. The following examples illustrate the invention.
Abbreviations : rpm: rounds per minute s: second(s)
Example 1 (melt granulate consisting of 10 % by weight of PEG 6000 and 90% of clopidogrel besylate)
Melt 22.4 g of PEG 6000 using a hot plate, until it has reached 800C. Place 201.3 g of clopidogrel besylate in a high-shear mixer. While stirring (400 rpm), pour the melted PEG into the bowl containing clopidogrel. Add 50 g of dry ice (in the form of dry snow) and increase the speed to 3000 rpm for 30 seconds. The resulting granulate has a temperature of about 15°C, and is sieved through 2.0 and 1.0 mm. Clopidogrel besylate used as a starting material is prepared as follows :
Step 1 : Manufacture of clopidogrel besylate 7 g (0.0228 mole) of dextro-rotatory methyl alpha-5 (4, 5, 6, 7- tetrahydro (3, 2-c) thieno pyridyl) (2-chlorophenyl) acetate (i.e. clopidogrel in the form of its free base) is dissolved in 100 ml of diethyl ether. To the obtained solution 30 ml of diethyl ether containing 4.78 g (0.03 mole) of anhydrous benzene sulfonic acid are added at room temperature (i.e. at 280C -
310C) . After complete addition the reaction mass is maintained at room temperature (28°C - 31°C) for 14 hours. The white solid is collected by filtration and dried at 50-60 0C in a vacuum oven whereupon 2.2 g of clopidogrel besylate are obtained in crystalline form (99.82% pure according to HPLC); DSC: onset at 127.45°C, peak at 135.690C.
Example 2 (melt granulate consisting of 30 % PEG 6000 and 70% clopidogrel besylate) Analogously as described in Example 1 the above melt granulate is obtained from 86.4 g of clopidogrel besylate, 201.3 g of PEG 6000, and 80 g of dry snow.
Example 3 (melt granulate consisting of 50 % PEG 6000 and 50% clopidogrel besylate)
Analogously as described in Example 1 the above melt granulate is obtained from 201.3 g of clopidogrel besylate and 201.3 g of PEG 6000, adding between 130 and 150 g of dry snow and increasing the speed of the mixer to 3000 rpm for 1 minute.
Example 4 (melt granulate consisting of 50 % PEG 4000 and 50% clopidogrel besylate)
Melt 201.3 g of PEG 4000 using a hot plate, until it has reached 76 0C. Place 201.3 g of clopidogrel besylate in a high-shear mixer. While stirring (600 rpm) , pour the melted PEG in the bowl containing the clopidogrel. Add 150 g of dry ice and increase the speed to 1800 rpm for 1 mn. The resulting granulate has a temperature of 17.6°C, and is sieved through 2.00 and 1.0 mm
Example 5 (melt granulate consisting of 50 % PEG 20000 and 50% clopidogrel besylate)
201.3 g of PEG 20000 are melted using a hot plate, until it has reached 1000C. 201.3 g of clopidogrel besylate are placed into a high-shear mixer. While stirring (400 rpm) the melted PEG is poured into the bowl containing the clopidogrel. 50 g of dry ice are added and the speed of the mixer is increased to 3000 rpm for 1 minute. The resulting granulate has a temperature of 15°C, and is sieved through 2.0 and 1.0 mm.
Example 6 (melt granulate consisting of 50 % by weight of PEG 35000 and 50% clopidogrel besylate)
Melt 201.3 g of PEG 35000 using a hot plate, until it has reached 100°C. Place 201.3 g of clopidogrel besylate in a high- shear mixer. While stirring (400 rpm), pour the melted PEG into the bowl containing the clopidogrel. Add 100 g of dry ice and increase the speed to 3000 rpm for 2 minutes. The resulting granulate has a temperature of 300C, and is sieved through 2.0 and 1.0 mm.
Example 7 (melt granulate consisting of 50 % by weight of PEG 6000 and 50% clopidogrel hydrochloride)
Melt 10.0 g of PEG 6000 using a 78°C water bath until it has reached 74°C. Place 10.0 g of clopidogrel hydrochloride into a mortar. While manually stirring, pour the melted PEG in the mortar containing the clopidogrel hydrochloride. Stir another 2 minutes, then let the resulting mass cool down to room temperature, before grinding it. Example 8 (melt granulate consisting of 50 % by weight of Compritol 888 ATO and 50% clopidogrel hydrochloride) Melt 10.0 g of Compritol 888 ATO using a 78°C water bath until it has reached 740C. Place 10.0 g of clopidogrel hydrochloride into a mortar. While manually stirring, pour the melted
Compritol into the mortar containing the clopidogrel. Stir another 2 minutes, then let the resulting mass cool down to room temperature, before grinding it.
Example 9 (storage stability of clopidogrel besylate and melt granulates containing it)
The stability on storage of clopidogrel besylate salt (CLO'Bes) is examined in comparison to melt granulates containing it. The main degradation product is alpha- (2-chlorophenyl) -4 , 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetic acid, hereinafter designated as "ImpA" (ImpA is named according to USP 29 and corresponds to the hydrolysis product of Clopidogrel) . In addition, the sum of all impurities ("Sumlmp") is determined. Both ImpA and Sumlmp are expressed as percent by weight of the amount of the clopidogrel salt at the beginning of the experiment on day 0 and are determined using the HPLC-system described below.
In the below Table 1 for example the term "10% PEG 6000" means the melt granulate consisting of 10% by weight PEG 6000 and 90% by weight clopidogrel besylate, 30% PEG 6000 means the melt granulate consisting of 30% by weight PEG 6000 and 70% by weight clopidogrel besylate, etc. Table 1
As evident from the above Table 1 clopidogrel besylate (CLO Bes) contains after storage for 15 days at 50 0C and 75% relative humidity on an average about 79 % (0.34/0.19 = 1.79) more of the impurity ImpA and about 41 % (0.52/0.37 = 1.41) more total impurities Sumlmp than the clopidogel besylate stabilized in the above melt granulates. The values of 0.19 and 0.37 mentioned herein above in parentheses and used for calculation are the averages of the values listed for the granulates in the columns ImpA and Sumlmp, respectively, on day 15.
The above-mentioned HPLC system is as follows:
Instruments and operating conditions: Column: 250 mm x 4.6 mm Modulo-Cart QS Uptisphere HDO, 3 μm
Detector: UV Detector or DAD Detector
Eluent A:0.01M sodium phosphate dibasic aqueous solution (1.78 g
Na2HPO4 * 2 H2O/1), adjusted to pH 3.0 ± 0.05 with phosphoric acid
85% Eluent B: Acetonitril
Mobile phase: 35% Eluent A + 65% Eluent B
Gradient :
Operating conditions: Flow rate: 0.4 ml/mm
Column temperature: 200C Infection volume: 10 μl Wavelength: 235 nm
Runtime: 65 mm
Retention time:
Preparation of reference and sample solutions: Reference solution
Approximately 55.92 mg of clopidogrel besilate reference substance are weighed into a 50 ml volumetric flask. Add 20 ml of mobile phase and sonicate m an ultrasonic bath at ambient temperature until the substance is dissolved (approx. 5 min) . Make up to the mark with mobile phase. The concentration of clopidogrel besilate is 0.75 mg/ml as free base. Two independent reference solutions are prepared.
Sample solution for 75 mg tablets
Weigh 10 tablets and transfer them quantitatively into a 250 ml volumetric flask. Dissolve and make up to the mark with mobile phase. Dilute 25.0 ml to 100.0 ml with mobile phase. Filter through a 0.45 μm PTFE-fliter in a HPLC vial. The concentration of clopidogrel is 0.75 mg/ml as free base. Two independent sample solutions are prepared. Example 10 (Storage stability of clopidogrel hydrochloride) The stability on storage of clopidogrel hydrochloride salt (CLO'HCl) has been examined in comparison to melt granulates containing it. The main degradation product is alpha- (2-chloro- phenyl) -4,5,6, 7-tetrahydrothieno [3, 2-c] pyridine-5-acetic acid, hereinafter designated as "ImpA" (impurity acid) . In addition, the sum of all impurities ("Sumlmp") is determined by HPLC analogously as described above for clopidogrel besylate. Both ImpA and Sumlmp are expressed as percent by weight of the amount of the clopidogrel salt at the beginning of the experiment on day 0. The granulates mentioned in the below Table 2 are melt granulates consisting of 50 % by weight of PEG 6000 and 50% clopidogrel hydrochloride, and 50 % Compritol 888 ATO and 50% clopidogrel hydrochloride, respectively. Table 2
As evident from the above Table 2 clopidogrel hydrochloride (CLO HCL) contains after storage for 30 days at 4O0C and 75% relative humidity on an average about 95% (1.28/0.655 = 1.95) more of the impurity ImpA (i.e. nearly twice as much) and about 92% (1.99/1.035 = 1.92) more total impurities Sumlmp than the clopidogrel hydrochloride stabilized in the above melt granulates .
Example 11 (manufacture of tablets from a melt granulate containing 50% by weight of clopidogrel besylate and 50% by weight of PEG 6000)
In a first step, the granulate is mixed with the excipients in order to form the final blend. 44.74 g of granulate are placed in a container. 26.74 g of Avicel® PH200 (microcrystalline cellulose), 3.80 g of Plasdone© XL (l-ethenylpyrrolidin-2-one) and 0.72 g of Cutina® HR (Hydrogenated Castor Oil) are added. The container is sealed and then the blend is mixed for 10 minutes so that it becomes homogeneous.
In a second step, the final blend is tabletted using 10 mm R9 round, biconvex punches. Each unit has a mass of 380 mg, and is tabletted so that its hardness is between 80 and IOON and its thickness between 5.4 and 6.0 mm.
Example 12 (manufacture of tablets comprising a melt granulate containing 50% by weight of clopidogrel besylate and 50% by weight of PEG 6000)
In an analogous manner as described in Example 11 tablets are manufactured whereby either the excipients may be added to the melt to form the melt granulate or all or part of the excipients is added to the granulate to be compressed into a tablet. The compositions are given in Table 3. The tablets obtained according to Example 11 or Example 12 are then coated with a composition as given in Table 4. Table 3
corresponding to about 75 mg Clopidogrel Base. Table 4
the isopropanol is evaporated
Example 13
In an analogous manner as described in Example 12 tablets are manufactured whereby either the excipients may be added to the melt to form the melt granulate or all or part of the excipients is added to the granulate to be compressed into a tablet. The compositions are given in Table 5. The tablets obtained are then coated with a composition as given in Table 4. The test results were as follows: ImpA [%] at Day 0: zero (no ImpA); ImpA [%] at Day 15 (500C, 75% relative humidity): 0.28.
Table 5
corresponding to about 75 mg Clopidogrel Base.

Claims

Claims
1. Melt granulate comprising clopidogrel or a pharmaceutically acceptable salt thereof.
2. Melt granulate according to claim 1 comprising a pharmaceutically acceptable salt of clopidogrel.
3. Melt granulate according to claim 1 comprising clopidogrel besylate or clopidogrel hydrochloride.
4. Melt granulate according to any one of claims 1-3 comprising a polyethylene glycol having a mean molecular weight from 1500 to 35000.
5. Melt granulate according to any one of claims 1-3 comprising a polyethylene glycol having a mean molecular weight from 4000 to 10000.
6. Melt granulate according to any one of claims 1-5 containing from 10 to 90 per cent by weight of clopidogrel or a pharmaceutically acceptable salt thereof.
7. Melt granulate according to any one of claims 1-5 containing from 10 to 90 per cent by weight of a pharmaceutically acceptable salt of clopidogrel and (100 minus x) per cent by weight of a polyethylene glycol having a mean molecular weight of from 2000 to 30000, wherein x is the content of the pharmaceutically acceptable salt of clopidogrel expressed as per cent by weight.
8. Melt granulate according to any one of the claims 1-7 in the form of a solid state dispersion of the drug in a pharmaceutically acceptable carrier, wherein said melt granulate comprises a pharmaceutically active compound, preferably clopidogrel, at least one carrier material, and optionally pharmaceutically acceptable excipients.
9. Melt granulate according to claim 8, wherein the optional pharmaceutically acceptable excipients is selected from the group comprising diluents, fillers, binders, disintegrants, coloring agents, flavoring agents, lubricants and preservatives.
10. Melt granulate according to any one of the claims 1 to 9, wherein the ratio of the drug to the pharmaceutically acceptable carrier is within the range of about 10% to 90% of the total solid dispersion weight, more preferable within the range of about 20% to 90%, more preferable within the range of about 40% to 90%, more preferable within the range of about 50% to 90%, of the total dispersion weight.
11. Method of making a melt granulate according to any one of the claims 8-10, characterized in that the pharmaceutically acceptable carrier is mixed with the pharmaceutically active compound, and optionally also with the pharmaceutically acceptable excipients, to form an intimate mixture, the obtained mixture is then heated at or near the temperature of the melting point of the pharmaceutically acceptable carrier but below the melting point of the pharmaceutically active compound, thus forming a melt, the obtained melt is then cooled rapidly to provide a congealed mass which optionally is milled to produce a powder.
12. Method of making a melt granulate according to any one of the claims 8-10, characterized in that the pharmaceutically acceptable carrier, optionally containing pharmaceutically acceptable excipients, is heated at or near the temperature of the melting point of the pharmaceutically acceptable carrier but below the melting point of the pharmaceutically active compound; the molten pharmaceutically acceptable carrier is then mixed with the pharmaceutically active compound until a homogeneous melt is formed; the obtained melt is then cooled rapidly to provide a congealed mass which optionally is milled to produce a powder.
13. Method according to claim 12, wherein the molten carrier is added to the drug under stirring or mixing.
14. Method according to any one of the claims 11 to 13, wherein cooling process is effected by conventional methods.
15. Method according to any one of the claims 11 to 13, wherein the cooling is effected by shock cooling, preferably by adding dry ice (i.e. solid carbon dioxide), preferably in the form of a kind of snow ("dry snow"), or liquefied air, preferably solid carbon dioxide, to the dispersion which thereupon cools rapidly and breaks apart into many small particles and optionally sieving the particles obtained to the desired average grain size.
16. Method according to any one of the claims 11 to 15, wherein the excipients is added to the melt and/or later to the solid state dispersion of the drug.
17. Pharmaceutical composition comprising a melt granulate as claimed in any one of claims 1-10.
18. Method of reducing atherothrombotic events in a human patient in case of recent myocardial infarction, recent stroke, established peripheral arterial disease, and acute coronary syndrome by administering to said patient an atherothrombotic events reducing effective amount of a pharmaceutical composition as claimed in claim 17.
EP07818184A 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel Not-in-force EP2068838B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP11003617A EP2359810A2 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel
PL07818184T PL2068838T3 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel
EP07818184A EP2068838B1 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06019429A EP1900358A1 (en) 2006-09-16 2006-09-16 Pharmaceutical formulations comprising clopidogrel
PCT/EP2007/008070 WO2008031623A1 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel
EP07818184A EP2068838B1 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP11003617.5 Division-Into 2011-05-03

Publications (2)

Publication Number Publication Date
EP2068838A1 true EP2068838A1 (en) 2009-06-17
EP2068838B1 EP2068838B1 (en) 2012-04-11

Family

ID=37735123

Family Applications (3)

Application Number Title Priority Date Filing Date
EP06019429A Withdrawn EP1900358A1 (en) 2006-09-16 2006-09-16 Pharmaceutical formulations comprising clopidogrel
EP07818184A Not-in-force EP2068838B1 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel
EP11003617A Withdrawn EP2359810A2 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP06019429A Withdrawn EP1900358A1 (en) 2006-09-16 2006-09-16 Pharmaceutical formulations comprising clopidogrel

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP11003617A Withdrawn EP2359810A2 (en) 2006-09-16 2007-09-17 Pharmaceutical formulations comprising clopidogrel

Country Status (16)

Country Link
US (1) US20090270448A1 (en)
EP (3) EP1900358A1 (en)
AT (1) ATE552826T1 (en)
AU (1) AU2007296854A1 (en)
CA (1) CA2663311A1 (en)
DE (1) DE202007019385U1 (en)
DK (1) DK2068838T3 (en)
ES (1) ES2384740T3 (en)
IL (1) IL197089A0 (en)
MX (1) MX2009002356A (en)
NO (1) NO20091467L (en)
NZ (1) NZ575153A (en)
PL (1) PL2068838T3 (en)
PT (1) PT2068838E (en)
RU (1) RU2009114206A (en)
WO (1) WO2008031623A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004106344A2 (en) 2003-04-25 2004-12-09 Cadila Healthcare Limited Salts of clopidogrel and process for preparation
EP1900358A1 (en) 2006-09-16 2008-03-19 Cimex Pharma AG Pharmaceutical formulations comprising clopidogrel
CN102240269B (en) * 2010-05-12 2013-04-10 天津泰普药品科技发展有限公司 Preparation method of crystalline clopidogrel bisulfate tablets
EP2585161A1 (en) * 2010-06-23 2013-05-01 Stefan Kralev Medical device for self-administration of patients with acute coronary events
CN107501289B (en) * 2017-09-07 2019-06-14 山东齐都药业有限公司 Preparation method of the bisulfate clopidogrel in relation to substance D
CN110339178B (en) * 2019-06-28 2021-07-02 广州白云山天心制药股份有限公司 Preparation method of clopidogrel hydrogen sulfate solid preparation
CN115737578A (en) * 2022-11-23 2023-03-07 石家庄四药有限公司 Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1900358A1 (en) 2006-09-16 2008-03-19 Cimex Pharma AG Pharmaceutical formulations comprising clopidogrel

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2530247B1 (en) 1982-07-13 1986-05-16 Sanofi Sa NOVEL THIENO (3, 2-C) PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION
FR2623810B2 (en) * 1987-02-17 1992-01-24 Sanofi Sa ALPHA SALTS- (TETRAHYDRO-4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -THETHYL ACETATE DEXTROGYRE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
US5308621A (en) * 1991-02-18 1994-05-03 Commonwealth Scientific And Industrial Research Organisation Ascorbic acid composition and transdermal administration method
JP3397385B2 (en) * 1993-09-20 2003-04-14 第一製薬株式会社 Disintegration delay prevention tablets
KR100768034B1 (en) * 1999-03-17 2007-10-17 다이이찌 세이야꾸 가부시기가이샤 Pharmaceutical composition
FR2792836B3 (en) * 1999-04-30 2001-07-27 Sanofi Sa PHARMACEUTICAL COMPOSITION IN UNIT FORM CONTAINING ASPIRIN AND CLOPIDOGREL HYDROGENOSULFATE
CA2363053C (en) 2001-11-09 2011-01-25 Bernard Charles Sherman Clopidogrel bisulfate tablet formulation
DE10305984A1 (en) * 2003-02-13 2004-09-02 Helm Ag Salts of organic acids with clopidogrel and their use in the manufacture of pharmaceutical formulations
DE10341264A1 (en) * 2003-09-04 2005-03-24 Grünenthal GmbH Melt-formulated, multiparticulate oral dosage form

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1900358A1 (en) 2006-09-16 2008-03-19 Cimex Pharma AG Pharmaceutical formulations comprising clopidogrel

Also Published As

Publication number Publication date
PT2068838E (en) 2012-06-27
EP2359810A2 (en) 2011-08-24
AU2007296854A1 (en) 2008-03-20
MX2009002356A (en) 2009-05-15
ES2384740T3 (en) 2012-07-11
EP2068838B1 (en) 2012-04-11
US20090270448A1 (en) 2009-10-29
PL2068838T3 (en) 2012-10-31
IL197089A0 (en) 2009-11-18
NZ575153A (en) 2011-01-28
ATE552826T1 (en) 2012-04-15
DK2068838T3 (en) 2012-07-09
EP1900358A1 (en) 2008-03-19
RU2009114206A (en) 2010-10-27
CA2663311A1 (en) 2008-03-20
NO20091467L (en) 2009-04-15
DE202007019385U1 (en) 2012-03-29
WO2008031623A1 (en) 2008-03-20

Similar Documents

Publication Publication Date Title
CA2800446C (en) Solid ivabradine-containing composition
EP2068838B1 (en) Pharmaceutical formulations comprising clopidogrel
AU2008244936B2 (en) Stable solid preparation comprising 4,5-epoxymorphinan derivative
JP2012512840A (en) Solid composition containing rasagiline component
EP2732810A1 (en) Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same
SK287869B6 (en) Beta-carboline pharmaceutical compositions
KR20090022616A (en) Oral administration drug, which contains clopidogrel besylate
KR20110074613A (en) Stable tablet containing 4,5-epoxymorphinan derivative
KR100988233B1 (en) Pharmaceutical composition and formulation comprising clopidogrel 1,5-naphthalene disulfonate or hydrate thereof
IL141766A (en) Olanzapine pamoate, solvates thereof and medicaments comprising them
JP2002538197A (en) Betahistine sustained release composition
JPH1192369A (en) Pharmaceutical preparation, its production and use of acidic additive for stabilization of cilansetron
US20080221079A1 (en) Pharmaceutical composition of quetiapine fumarate
EP2559431A1 (en) Pharmaceutical composition comprising 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide
EP1802280A2 (en) Clopidogrel compositions
CA2675538C (en) Oral pharmaceutical compositions comprising unmicronized nebivolol or a nebivolol analogue as active ingredient, and a decreased ratio of wetting agent to active ingredient
EP1716848B1 (en) Solid pharmaceutical composition containing a crystalline derivative of piperidine substituted in the 1,4 position
US20080194560A1 (en) Disintegration promoters in solid dose wet granulation formulations
CZ298604B6 (en) Solid form pharmaceutical mixture suitable for making tablets therefrom and containing profen
KR20160082170A (en) An oral solid formulation containing rivaroxaban
WO2014157603A1 (en) Pharmaceutical composition for oral administration
EP2543362A1 (en) Sustained release pharmaceutical oral solid dosage form of dronedarone or one of its pharmaceutically acceptable salts

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090416

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20090803

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ACINO PHARMA AG

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 552826

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120415

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602007021983

Country of ref document: DE

Effective date: 20120606

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20120620

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: ACINO PHARMA AG

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2384740

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20120711

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20120411

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20120401473

Country of ref document: GR

Effective date: 20120903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120811

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FI

Payment date: 20120919

Year of fee payment: 6

Ref country code: GB

Payment date: 20120920

Year of fee payment: 6

Ref country code: SE

Payment date: 20120920

Year of fee payment: 6

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: DORNACHERSTRASSE 114, 4147 AESCH (CH)

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20121008

Year of fee payment: 6

Ref country code: NL

Payment date: 20120920

Year of fee payment: 6

Ref country code: DE

Payment date: 20121130

Year of fee payment: 6

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20130114

BERE Be: lapsed

Owner name: ACINO PHARMA A.G.

Effective date: 20120930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120930

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602007021983

Country of ref document: DE

Effective date: 20130114

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20120401473

Country of ref document: GR

Effective date: 20130404

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20130617

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120711

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120930

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120917

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130404

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120917

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130617

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20131022

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 552826

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120917

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120917

REG Reference to a national code

Ref country code: PL

Ref legal event code: LAPE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120917

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20140401

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130917

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130918

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20140319

Year of fee payment: 7

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20130930

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20130917

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120918

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120917

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602007021983

Country of ref document: DE

Effective date: 20140401

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20140530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20070917

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130917

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140401

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140930

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140930